The field of this invention is pharmacology.
Any chemical agent that affects any process of living is a drug. Drugs are a critical tool for health care practitioners, as they are used in the prevention, diagnosis and treatment of disease. Because of their criticality to the health care profession, annual world investment into the research and development of new chemical agents with therapeutic potential reaches into the billions of dollars. As a result, a large number of drugs have been developed to date and new chemical agents having potential therapeutic utility are frequently discovered. Chemical agents that find, or have found, use as drugs include naturally occurring and synthetic small molecules, as well as larger molecules, such as proteinaceous compounds.
Most small molecule drugs cause a pharmacological effect by binding to a target protein and altering the pharmacological activity of the target in some way. For a given small molecule drug, it is desirable that the drug have at least one of high affinity and specificity for its target. If a small molecule has high affinity for its target, it is characterized by having good binding to its target. If a small molecule has specificity for its target, it is characterized by having differential affinity between its target and other, non-target proteins. Besides displaying high affinity and/or specificity, a given small molecule should be selective with respect to the cell or tissue in which it affects a biological activity. Selectivity will assure that the drug target will be affected by the drug only in cells involved in the disease process.
Screens for small molecule drugs rarely identify high affinity ligands, low affinity ligands with high specificity or selective ligands. Much more often, compounds are identified that have biological activity but with relatively low affinity and low specificity for their targets. Furthermore, identified compounds usually lack selectivity for their targets with respect to cell or tissue type. Because of this low affinity, specificity, or selectivity or combination thereof, these identified ligands never find clinical use.
As such, of great interest to the pharmaceutical industry and related fields would be the development of a method for increasing at least one of the affinity, specificity and selectivity of these previously identified biologically active agents, such that agents that otherwise lack sufficient affinity and/or specificity nonetheless could find clinical utility.
Relevant Literature
Patent publications of interest include: WO 91/01743; WO 94/18317; WO 95/02684; WO 95/10302; WO 96/06111; WO 96/12796; WO 96/13613; WO 97/25074; WO 97/29372; WO 98/11437; WO 98/47916; U.S. Pat. Nos. 5,830,462; 5,843,440; and 5,871,753. References of interest include: Briesewitz et al., Proc. Nat""l Acad. Sci. USA (March 1999) 96: 1953-1958; Clardy, Proc. Nat""l Acad. Sci. USA (March 1999) 1826-1827; Crabtree and Schreiber, Elsevier Trends Journal (November 1996) 418-422; Spencer et al., Curr. Biol. (July 1996) 6:839-847; Spencer et al., Science (1993) 262: 1019; Chakraborty et al., Chem. and Biol. (March 1995) 2:157-161; Ho et al., Nature (1996) 382: 822; Riviera et al., Nature Medicine (1996) 2: 1028; Klemm et al., Current Biology (1997) 7: 638; Belshaw et al., Proc. Nat""l. Acad. Sci. USA (1996) 93: 4604; Livnah et al., Science (1996) 273: 464; Johnson et al., Chemistry and Biology, (1997) 4: 939; Garboczi et al., Nature (1996) 384:134; Kissenger et al., Nature (1995) 378:641; Griffith et al., Cell (1995) 82: 507; Choi et al., Science (1996) 273:239. Also of interest are Kramer et al., J. Biol. Chem. (1992) 267:18598-18604; and Varshavsky, Proc. Nat""l Acad. Sci. USA (March 1998) 95: 2094-2099; Varshavsky, Proc. Nat""l Acad. Sci. USA (April 1995) 92:3663-3667; and Mu et al., Biochem. Biophys. Res. Comm. (1999)255:75-79.
Bifunctional molecules capable of producing at least a binary complex with a host endogenous presenter protein are provided. In the subject methods, a bifunctional molecule is synthesized by covalently linking an endogenous presenter protein ligand to a drug moiety, either directly or through a linking group. An effective amount of a bifunctional molecule is administered to the host, where the bifunctional molecule binds to the endogenous presenter protein to produce the binary complex. The resultant binary complex modulates (e.g. enlarges) the target binding surface area of the drug moiety, i.e. the surface area available for binding with the target, in a manner such that at least one of enhanced affinity, specificity or selectivity are observed as compared to that observed with the free drug.
In one embodiment where the binary complex results in enhanced affinity, a tripartite complex is produced in which binding interactions are present between the presenter and target as well as the drug moiety and target. In a second embodiment where the binary complex results in enhanced specificity, delivery of the drug as a bifunctional molecule results in differential affinity with respect to its potential targets such that the drug moiety binds more to its desirable target than to its undesirable targets as compared to a free drug control situation, e.g. where tripartite complexes produced between the binary complex and undesired targets are characterized by the presence of unfavorable interactions while tripartite complexes produced between the binary complex and the desired target are characterized by the presence of no interactions, neutral interactions or favorable interactions. In a third embodiment where the binary complex results in enhanced selectivity, tripartite complexes produced with undesired targets in a first cell or tissue type are characterized by the presence of unfavorable interactions while the bifunctional molecule affects the desired target in a second cell or tissue type, e.g. a second type of cell or tissue in the same organism or a microorganism in a host organism, without formation of a binary complex between the bifunctional molecule and a presenter protein due to the lack of the presenter protein.
The subject methods and compositions find use in a variety of therapeutic applications.